ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.94C>G (p.Leu32Val)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000371.4(TTR):c.94C>G (p.Leu32Val)
Variation ID: 1075407 Accession: VCV001075407.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31592920 (GRCh38) [ NCBI UCSC ] 18: 29172883 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 10, 2021 Feb 14, 2024 May 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.94C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Leu32Val missense NC_000018.10:g.31592920C>G NC_000018.9:g.29172883C>G NG_009490.1:g.6154C>G LRG_416:g.6154C>G LRG_416t1:c.94C>G - Protein change
- L32V
- Other names
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- Canonical SPDI
- NC_000018.10:31592919:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TTR | - | - |
GRCh38 GRCh37 |
369 | 416 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Feb 24, 2022 | RCV001389002.6 | |
Pathogenic (1) |
criteria provided, single submitter
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May 14, 2021 | RCV002377579.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 23, 2023 | RCV003447595.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002688387.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.L32V pathogenic mutation (also known as c.94C>G), located in coding exon 2 of the TTR gene, results from a C to G substitution at … (more)
The p.L32V pathogenic mutation (also known as c.94C>G), located in coding exon 2 of the TTR gene, results from a C to G substitution at nucleotide position 94. The leucine at codon 32 is replaced by valine, an amino acid with highly similar properties. This variant (also referred to as p.L12V) has been detected in unrelated index cases with transthyretin amyloidosis with features including polyneuropathy and cardiomyopathy, and was reported to segregate with disease in a family (Martínez-Ulloa PL et al. J Peripher Nerv Syst, 2017 09;22:208-212; Hinderhofer K et al. Amyloid, 2019 Jun;26:85-93). Other variants affecting this codon (e.g., p.L32P and p.L32M) have also been reported in association with amyloidosis (Brett M et al. Brain. 1999 Feb;122 ( Pt 2):183-90; Choi K et al. J Clin Neurol. 2018 Oct;14(4):537-541). Based on internal structural analysis, the p.L32V variant is anticipated to result in a decrease in structural stability (Schormann N et al. Amyloid. 1998 Sep;5(3):175-87). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Amyloidosis
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175667.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The TTR c.94C>G variant is classified as Pathogenic (PS3, PM1, PM2, PS4_Supporting, PP3) The TTR c.94C>G variant is a single nucleotide change in exon 2/4 … (more)
The TTR c.94C>G variant is classified as Pathogenic (PS3, PM1, PM2, PS4_Supporting, PP3) The TTR c.94C>G variant is a single nucleotide change in exon 2/4 of the TTR gene, which is predicted to change the amino acid leucine at position 32 in the protein, to valine. The variant has been reported in 4 probands with a clinical presentation of Amyloid polyneuropathy and has been reported to segregate in 2 affected family members (PMID#28646538, 31074293) (PS4_Supporting) . Functional studies using isoelectric focussing of the WT and mutant TTR protein, showed differences in tetramer and monomer stability compared with WT indicating this variant has an impact on the resultant protein (PMID#31074293)(PS3). Multiple changes to the same amino acid (p.Leu32M/P) have been reported in individuals with TTR-related disease suggesting changes to this amino acid are not tolerated (PM1). This variant is absent from population databases (PM2), is not reported in dbSNP, is reported as disease causing in the HGMD database (CM179391) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 1075407). Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
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Pathogenic
(Feb 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001590203.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant disrupts the p.Leu32 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10071047, 15820680, … (more)
This variant disrupts the p.Leu32 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10071047, 15820680, 20209591, 25488473). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function. ClinVar contains an entry for this variant (Variation ID: 1075407). This variant is also known as Leu12Val. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 28646538, 31074293). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 32 of the TTR protein (p.Leu32Val). (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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New sequence variants in patients affected by amyloidosis show transthyretin instability by isoelectric focusing. | Hinderhofer K | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2019 | PMID: 31074293 |
A novel ATTR L32V mutation causes familial amyloid polyneuropathy in a Bolivian family. | Martínez-Ulloa PL | Journal of the peripheral nervous system : JPNS | 2017 | PMID: 28646538 |
Oculoleptomeningeal Amyloidosis associated with transthyretin Leu12Pro in an African patient. | McColgan P | Journal of neurology | 2015 | PMID: 25488473 |
Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: a single-center experience. | Barreiros AP | Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society | 2010 | PMID: 20209591 |
The biological and chemical basis for tissue-selective amyloid disease. | Sekijima Y | Cell | 2005 | PMID: 15820680 |
Transthyretin Leu12Pro is associated with systemic, neuropathic and leptomeningeal amyloidosis. | Brett M | Brain : a journal of neurology | 1999 | PMID: 10071047 |
Tertiary structures of amyloidogenic and non-amyloidogenic transthyretin variants: new model for amyloid fibril formation. | Schormann N | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 1998 | PMID: 9818054 |
Text-mined citations for rs2144406525 ...
HelpRecord last updated Mar 23, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.